Dataset Information

The ambiguous Caveolin-3 G55S sequence variant: Muscle biopsy findings and cell biological analysis

ABSTRACT: Caveolins are structural and functional proteins in plasma membrane invaginations called caveolae. Mutations in Caveolin-3 cause myopathies of variable severity. The pathogenicity of the Caveolin-3 variant G55S is still unclear. Here, we report on three patients suffering from mild to moderate myopathy. In all three patients, but also in two seemingly unaffected family members of patient one the G55S variant was found. Histology revealed moderate chronic myopathic changes and reduced sarcolemmal Caveolin-3 immunoreactivity in all three cases. Immunoblots for Caveolin-3 were abnormal in all cases. By electron microscopy, enlarged caveolae were detected in case one and three and vacuolar myopathy in case two. EM studies of RCMH myoblasts transfected with G55S Caveolin-3 revealed autophagic vacuoles. The alterations in Golgi morphology were in line with pathological Caveolin-3 deposits in this organelle detected by immunofluorescence and indicative for activation of autophagy. Phospho-blotting demonstrated that G55S affects EGFR signaling. Proteomic profiling of transfected RCMH myoblasts demonstrated alterations in levels of physiologically relevant proteins which are indicative for antagonization of G55S Caveolin-3 expression. Some proteomic alterations were enhanced by osmotic/mechanical stress. In conclusion, our results suggest that the G55S Caveolin-3 sequence variant can be compensated by cellular defense mechanisms and that additional stress may lead to vulnerability of G55S Caveolin-3 expressing muscle cells.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Smooth Muscle Myoblast

DISEASE(S): Myopathy

SUBMITTER: Laxmikanth Kollipara

LAB HEAD: Dr. René Zahedi

PROVIDER: PXD003719 | Pride | 2018-07-05

REPOSITORIES: Pride

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The Caveolin-3 G56S sequence variant of unknown significance: Muscle biopsy findings and functional cell biological analysis.

Brauers Eva E Roos Andreas A Kollipara Laxmikanth L Zahedi René P RP Beckmann Alf A Mohanadas Nilane N Bauer Hartmut H Häusler Martin M Thoma Stéphanie S Kress Wolfram W Senderek Jan J Weis Joachim J

Proteomics. Clinical applications 20161114 1-2

<h4>Purpose</h4>In the era of next-generation sequencing, we are increasingly confronted with sequence variants of unknown significance. This phenomenon is also known for variations in Caveolin-3 and can complicate the molecular diagnosis of the disease. Here, we aimed to study the ambiguous character of the G56S Caveolin-3 variant.<h4>Experimental design</h4>A comprehensive approach combining genetic and morphological studies of muscle derived from carriers of the G56S Caveolin-3 variant were c ...[more]

PMID: 27739254

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